A mutation in the beta-3-adrenergic receptor gene (Trp64Arg), common in many ethnic populations, has an association with early onset of non- insulin dependent diabetes mellitus, elevated insulin levels, increased body mass index, and other features of the insulin resistance syndrome. To better characterize the physiology of these alterations, we will study the differences in glucose matabolism, body composition, and energy expenditure in: 1) individuals with two copies of the normal allele, individuals with two copies of the mutant allele, and individuals who are heterozygous for the variant receptor. We will determine the body composition using CT scan for visceral fat measurements, anthropomorphic measurements, and DEXA scan to determine fat mass. Glucose tolerance will be determined using IV glucose tolerance tests and the MINMOD analysis program. Energy expenditure will be determined using indirect calorimetry and doubly- labeled water method, and compared between the three groups. Individual measurements will be collated into a database and quantitative traits will be compared between the three groups by analysis of variance, and, where appropriate, analysis of covariance. Genotyping of patients began in the sumer of 1995. The first patient was studied in the summer of 1996. Since that time, we have genotyped over 1800 individuals, and have enrolled 26 into the GCRC physiologic studies. Our total goal is 4000 genotpyes and 75-80 subjects enrolled in the GCRC-approved project with a completion date targeted for the summer of 2000. Preliminary analysis reveals a significant association (p=0.01) with low levels of glucose effectiveness, i.e., direct effect of glucose on tissue, and a strong trend towards low levels of insulin secretion (p=0.08) in individuals who are homozygous for the mutation. This suggests a direct role of lower sympathetic nervous system activity as influenced by the variant allele altering glucose metabolism.